Project Summary The acquisition and persistence of an aversive memory is a central component of fear-based disorders such as post-traumatic stress disorder. Pavlovian fear conditioning uses neutral cues that predict the occurrence of an aversive event, typically a mild electric shock. After pairings of the cue with shock, organisms will exhibit behaviors that are consistent with the expression of fear, and which we measure to infer that learning has taken place. This form of learning is widely used as a model system for studying how fear-based memories are formed, and the study of fear conditioning has yielded detailed knowledge regarding the cellular and molecular mechanisms necessary for fear memory formation. Much of this work has used training procedures in which memories were acquired in isolation from other controlled experiences. However, memories are not normally acquired in isolation from other experiences, and in fact can be influenced by prior experiences. As an example, our previous studies have showed that prior fear conditioning can facilitate the acquisition of new fears when another cue is presented and paired with shock hours or days later. Given the profound influence of prior experience, identifying the mechanisms by which past experience impacts later learning is essential to our understanding of learning and memory. Our long-term goal is to understand the neurobiological mechanisms that allow prior fear conditioning to alter subsequent fear learning. The objective in this proposal is to determine whether or not changes in the expression of specific ion channel proteins are required for the ability of the initial experience to prime subsequent learning, memory formation for an initial experience, or both processes. Our hypothesis is that changes in expression of sodium channels containing the 1-beta subunit, and Kv4.2 potassium channels, play a specific role in the priming of future learning, but are not required for memory formation or the expression of fear behavior. To achieve this objective, we will combine behavioral studies, with protein and RNA expression analysis, and site-specific RNA interference. In specific Aim 1, we will test if the ability of an initial fear conditioning trial to prime later learning depends on altered expression of sodium channels containing the 1-beta subunit in the basolateral amygdala. In specific Aim 2, we will test the involvement of the Kv4.2 potassium channel. This project is focused on describing the neural mechanisms that allow prior experience prime future memory formation. The basic information gained here has implications for the etiology of fear-based disorders and ultimately may open up new avenues for their treatment.